Controlled released compositions

ABSTRACT

The compositions disclosed herein are for use as controlled release therapeutics for the treatment of a wide variety of diseases. In particular, the compositions provide water soluble bioactive agents, organic ions and polymers where the bioactive agent is efficiently released over time with minimal degradation products. The resulting controlled release composition is capable of administration in a decreased dose volume due to the high drug content and predominance of non-degraded bioactive agent after release. Additionally, the compositions, of the present invention are capable of long term, sustained releases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase application filed under 35 U.S.C. §371 of PCT Application Number PCT/US2004/022817, filed Jul. 15, 2004,which claims priority from U.S. Provisional Patent Application No.60/489,402, filed Jul. 23, 2003.

In the table on pages 19-21, in the 3^(rd) column, replace the word“cylated” with the words “% Acylated”.

FIELD OF THE INVENTION

The present invention relates to controlled release compositionsincluding a water soluble bioactive agent, an organic ion and a polymer,wherein the content of said bioactive agent is about two to four foldhigher than in the absence of organic ion.

BACKGROUND OF THE INVENTION

Currently there are numerous controlled release formulations on themarket that contain various bioactive agents, such as GnRH analogs,human growth hormone, risperidone, and somatostatin analogs of whichoctreotide acetate is an example. Such formulations are preferred byphysicians and veterinarians and by their patients because they reducethe need for multiple injections. Unfortunately, there are many problemswith the formulations for controlled release compositions such as thefact that many popular bioactive agents are not good candidates forcontrolled release compositions due to their substantial watersolubility. The use of highly soluble bioactive agents may result in lowdrug content and an undesirable “burst” of bioactive agent upon contactwith an aqueous solution, such as by administration to a patient orintroduction to a physiological medium, which often limits the useablecontent of bioactive agent achievable in practice.

Various methods of solving the water solubility problem have beendevised with some success. One such effort is disclosed in U.S. Pat. No.5,776,885 by Orsolini et al. Orsolini converted water soluble peptidesto their water insoluble addition salts with pamoic, tannic or stearicacid prior to their encapsulation in sustained release compositions.Encapsulation within a polymer matrix is then performed by dispersingthe water insoluble peptide in a polymer solution and forming controlledrelease compositions via either extrusion or a cumbersome coacervationmethod. One disadvantage of this approach is the requirement to obtainthe water insoluble addition salt prior to encapsulation within apolymer matrix. Furthermore, it was discovered in the present work thatwhen pre-formed addition salts were employed in an emulsion process toform microparticles the result was release of substantial amounts ofmodified or degraded peptide from the composition when placed in anaqueous physiological buffer. Modification was in the form ofundesirable acylation of bioactive agent.

Controlled release compositions with a high drug load, low burst effectupon administration, and minimum degradation of the bioactive agent aregreatly needed to realize the benefits of these types of compositions ashuman or veterinary therapeutics.

SUMMARY OF THE INVENTION

It has now been discovered that controlled release compositions capableof administration in a concentrated, low dose volume form which releaseactive agent for a prolonged period of time can originate from watersoluble bioactive agents without first converting them to a waterinsoluble form. This finding is in direct contrast to previous work inthis field that suggested that water soluble bioactive agents would needto be manipulated in some way, for example to render them waterinsoluble, prior to forming a sustained release composition.Additionally, the conversion process required in previous compositions,resulted in a high percentage of degradation of the bioactive agent,whereas the compositions of the present invention are prepared with anunderstanding of how to reduce degradation. The presence of thebioactive agent in a physiologically relevant form creates an increasedcore load with regard to previously prepared compositions, which aresusceptible to significant degradation. Reduced degradation translatesinto increased release of unmodified bioactive agent, thus allowing fora smaller injection volume to deliver the same dose of bioactive agent.The compositions of the present invention offer a vast improvement overprevious inventions in that they provide a way to deliver a relativelyundegraded bioactive agent over a prolonged period of time using areduced dose volume.

In one embodiment, the controlled release compositions aremicroparticles and nanoparticles. In a particular embodiment, themicroparticles and nanoparticles are biodegradable. In anotherparticular embodiment, the polymer is selected from the group consistingof, but not limited to, poly(lactide)s, poly(glycolide)s,poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s,poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates,polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters,polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s,poly(alkylene alkylate)s, copolymers of polyethylene glycol andpolyorthoester, biodegradable polyurethanes, blends and copolymersthereof.

In another embodiment, the bioactive agent is selected from the groupconsisting of, but not limited to, proteins, nucleic acids,carbohydrates, peptides, small molecule pharmaceutical substances,immunogens, metabolic precursors capable of promoting growth andsurvival of cells and tissues, antineoplastic agents, hormones,antihistamines, cardiovascular agents, anti-ulcer agents,bronchodilators, vasodilators, central nervous system agents, narcoticantagonists and the like.

In a certain embodiment, the organic ion is selected from the groupconsisting of anionic and cationic materials. In a particularembodiment, the organic ion is selected from pamoate,trifluoromethyl-p-toluate, cholate, 2-naphthalene sulfonate,2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate,3-hydroxy-2-naphthoate, 2-naphthoate and salicylsalicylate.

In another embodiment, degradation includes acylation of the bioactiveagent or lysis of the polymer. In a particular embodiment the acylationreaction involves nucleophilic attack of an amino group of a bioactiveagent directed to a carbonyl carbon of a polyester such aspoly(d,l-lactide-co-glycolide). It is hypothesized that degradation ofthe bioactive agent is prevented or reduced in the present compositionsby facilitated protonation of potential nucleophiles (e.g., aminogroups), thus rendering the nucleophiles less apt to participate inacylation reactions with the PLGA polymer backbone or fragments thereof.

In another embodiment, the molar stoichiometry of the bioactive agentrelative to the organic ion ranges from about 0.5 to 2.0. In aparticular embodiment the molar stoichiometry of the bioactive agentrelative to the organic ion ranges from about 1.0 to 1.5.

In another certain embodiment, the present invention provides acontrolled release composition including a polymer and a bioactive agentin the form of a complex with an organic ion. Such a complex may beformed when an organic ion and a bioactive agent form a close physicalassociation.

In another embodiment the bioactive agent content may be increasedrelative to the bioactive agent content of compositions prepared by themethod of the present invention in the absence of an organic ion.

In a particular embodiment, the bioactive agent is octreotide acetateand the organic ion is pamoate. In another particular embodiment, thebioactive agent is water soluble.

In another embodiment the bioactive agent content may be increasedrelative to the bioactive agent content of previously preparedcompositions.

In another embodiment the core load of present compositions is greaterthan about 9% and/or the percentage of degraded product is about 25% orless.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention as claimed.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Definitions

For the purposes of the present invention, the following terms shallhave the following meanings:

For the purposes of the present invention, the term “biodegradable”refers to polymers that dissolve or degrade in vivo within a period oftime that is acceptable in a particular therapeutic situation. Suchdissolved or degraded product may include a smaller chemical species.Degradation can result, for example, by enzymatic, chemical and/orphysical processes. Biodegradation takes typically less than five yearsand usually less than one year after exposure to a physiological pH andtemperature, such as a pH ranging from 6 to 9 and a temperature rangingfrom 22 C to 38 C.

For the purposes of the present invention, the term “organic phase”refers to the solution of solvent, polymer and bioactive agent createdin the methods of the present invention that will then be contacted withan aqueous phase in order to create the controlled release compositionsof the present invention.

For the purposes of the present invention, the term “degradation” refersto any unwanted modification to the bioactive agent, such as acylation,or modification of the polymer such as lysis.

For the purposes of the present invention, the term “aqueous phase”refers to the solution of water and organic ion agent created in themethods of the present invention that will then be contacted with anorganic phase in order to create the controlled release compositions ofthe present invention.

For the purposes of the present invention, the term “combining” refersto any method of putting two or more materials together. Such methodsinclude, but are not limited to, mixing, blending, commingling,concocting, homogenizing, incorporating, intermingling, fusing, joining,shuffling, stirring, coalescing, integrating, confounding, joining,uniting, and the like.

For the purposes of the present invention, ranges may be expressedherein as from “about” or “approximately” one particular value, and/orto “about” or “approximately” another particular value. When such arange is expressed, another embodiment includes from the one particularvalue and/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms another embodiment. Itwill be further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint.

For the purposes of the present invention, the term “bioactive agent”refers to any agent with biological activity either in vivo or in vitro,where biological activity may be detected as an observable change inoverall health or at least one health marker (i.e., symptom) of anindividual, as a change in a relevant surrogate biological marker or asa change in the chemical structure or conformation of a physiologicallyrelevant molecule.

For the purposes of the present invention, the term “organic ion” refersto a cationic or anionic material. Organic ions may be present in theirsalt or acid forms. Exemplary organic ions include pamoate, naphthoate,cholate and the like.

For the purposes of the present invention, a “controlled releasecomposition” shall refer to any formulation with a different releaseprofile than native bioactive agent. Typically release profiles willinclude physiologically detectable concentrations of a bioactive agentover a period of at least one week, at least one month, at least 45days, or for longer than 45 days.

Moreover, for the purposes of the present invention, the term “a” or“an” entity refers to one or more of that entity; for example, “aprotein” or “an peptide” refers to one or more of those compounds or atleast one compound. As such, the terms “a” or “an”, “one or more” and“at least one” can be used interchangeably herein. It is also to benoted that the terms “comprising,” “including,” and “having” can be usedinterchangeably. Furthermore, a compound “selected from the groupconsisting of” refers to one or more of the compounds in the list thatfollows, including mixtures (i.e. combinations) of two or more of thecompounds. According to the present invention, an isolated orbiologically pure bioactive agent is a compound that has been removedfrom its natural milieu. As such, “isolated” and “biologically pure” donot necessarily reflect the extent to which the compound has beenpurified. An isolated compound of the present invention can be obtainedfrom its natural source, can be produced using molecular biologytechniques or can be produced by chemical synthesis.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingExamples section.

Controlled release compositions of the present invention include thefollowing disclosed components. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collective permutationof these compounds may not be explicitly disclosed, each is specificallycontemplated and described herein. For example, if a number of bioactiveagents are disclosed and discussed and a number of modifications thatcan be made to a number of molecules including bioactive agents arediscussed, specifically contemplated is each and every combination andpermutation of bioactive agent and the modifications that are possibleunless specifically indicated to the contrary. Thus, if a class ofmolecules A, B, and C are disclosed as well as a class of molecules D,E, and F and an example of a combination molecule, A-D is disclosed,then even if it is not individually recited each is individually andcollectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F,C-D, C-E and C-F are considered disclosed. Likewise, any subset orcombination of these is also disclosed. Thus, for example, the sub-groupof A-E, B-F, and C-E would be considered disclosed. This concept appliesto all aspects of this application including, but not limited to, stepsin methods of making and using the present invention.

Bioactive Agents

In one embodiment of the present invention, the bioactive agent isselected from the group consisting of a protein, a nucleic acid, acarbohydrate, a peptide or a small molecule pharmaceutical substance.Proteins of use in the present invention include but are not limited toantibodies, therapeutic proteins, human growth hormone, interferonalpha, interferon beta, interferon gamma, insulin, calcitonin,interleukin-1, interleukin-2, and the like. Nucleic acids of use in thepresent invention include DNA, RNA, chemically modified DNA andchemically modified RNA, aptamers, antisense, RNA interference, andsmall RNA interference. Carbohydrates include heparin, low molecularweight heparin and the like. Peptides include LHRH agonists andsynthetic analogs thereof, somatostatin and synthetic analogs thereof,hormones, octreotide, glucagon-like peptide, oxytocin and the like.Small molecule pharmaceutical substances include, but are not limitedto, antiinfectives, cytotoxics, antihypertensives, antifungal agents,antipsychotics, antidiabetic agents, immune stimulants, immunesuppressants, antibiotics, antivirals, anticonvulsants, antihistamines,cardiovascular agents, anticoagulants, hormones, antimalarials,analgesics, anesthetics, steroids, nonsteroidal anti-inflammatories,antiemetics.

In another embodiment, the bioactive agent is an immunogen. Suchimmunogen may be selected from the group consisting of, but not limitedto, immunogens for stimulating antibodies against hepatitis, influenza,measles, rubella, tetanus, polio, rabies, and the like.

In another embodiment, the bioactive agent is a substance or metabolicprecursor capable of promoting growth and survival of cells and tissuesor augmenting the functioning of cells. Such substance or metabolicprecursor may be selected from the group consisting of, but not limitedto, a nerve growth promoting substance such as a ganglioside, a nervegrowth factor, and the like; a hard or soft tissue growth promotingagent such as fibronectin, human growth hormone, a colony stimulatingfactor, bone morphogenic protein, platelet-derived growth factor,insulin-derived growth factors, transforming growth factor-alpha,transforming growth factor-beta, epidermal growth factor, fibroblastgrowth factor, interleukin-1, vascular endothelial growth factor,keratinocyte growth factor, dried bone material, and the like.

In another embodiment, the bioactive agent is an antineoplastic agent.In a particular embodiment, the antineoplastic agent is selected fromthe group consisting of, but not limited to, methotrexate,5-fluorouracil, adriamycin, vinblastin, cisplatin, tumor-specificantibodies conjugated to toxins, tumor necrosis factor, and the like.

In other embodiments, the bioactive agent is selected from the groupconsisting of, but not limited to, antihistamines such asdiphenhydramine, and the like; cardiovascular agents such as papverine,fibrinolytics such as streptokinase and the like; anti-ulcer agents suchas isopropamide iodide, and the like; bronchodilators such asmetaproternal sulfate, aminophylline, and the like; vasodilators such astheophylline, niacin, minoxidil, and the like; central nervous systemagents such as tranquilizers, β-adrenergic blocking agents, dopamine,and the like; antipsychotic agents such as risperidone, narcoticantagonists such as naltrexone, naloxone, buprenorphine; and other likesubstances.

In a certain embodiment, the bioactive agent is capable of providing alocal or systemic biological, physiological or therapeutic effect in thebiological system in which it is applied. For example, the agent may actto control infection or inflammation, enhance cell growth and tissueregeneration, control tumor growth and enhance bone growth, among otherfunctions.

In another embodiment, controlled release compositions may containcombinations of two or more bioactive agents. In a particularembodiment, controlled release compositions contain five or fewerbioactive agents. In another particular embodiment, controlled releasecompositions contain one bioactive agent.

In another embodiment, a “pharmaceutical equivalent” of a bioactiveagent is any compound with similar or greater in vitro activity to thebioactive agent itself. In a particular example, a pharmaceuticalequivalent has a similar chemical structure to the bioactive agent,contains only the biologically active portion of the bioactive agent oris a synthetic analog of the bioactive agent.

In another embodiment, bioactive agents of the present invention mayinclude various salt forms and derivatives including covalent linkagesto hydrophilic polymers such as poly(ethylene glycol) and poly(propyleneglycol).

In a particular embodiment, the bioactive agent has the potential toexhibit at least one positive or negative charge or both positive andnegative charge.

In a particular embodiment, the bioactive agent is water soluble.

In another particular embodiment, the bioactive agent is solubilized inan organic solvent, optionally including a cosolvent. The bioactiveagent may be soluble in water or in organic solvents or both.

It will be appreciated by one skilled in the art that the actual amountsof bioactive agents to utilize in a particular case will vary accordingto the specific compound being utilized, the particular compositionsformulated, the mode of application, and the particular situs andpatient being treated. Dosages for a given host can be determined usingconventional considerations, for example, by customary comparison of thedifferential activities of the subject compounds and of a knownbioactive agent, for example, by means of an appropriate conventionalpharmacological protocol. Physicians and formulators, skilled in the artof determining doses of pharmaceutical compounds, will have no problemsdetermining dose according to standard recommendations.

Organic Ion

Organic ions of use in the present invention include anionic andcationic materials. Anionic materials include, but are not limited to,the following organic acids and their salts: pamoic, dodecylsulfuric,cholic, trifluoromethyl-p-toluic, 2-naphthalene sulfonic,2,3-naphthalene dicarboxylic, 1-hydroxy-2-naphthoic,3-hydroxy-2-naphthoic, 2-naphthoic, and salicylsalicylic. Salt forms ofthe anionic materials may include, sodium, ammonium, magnesium, calciumand the like.

Cationic molecules include, but are not limited to, those having anammonium or guanidinium group or a substituted ammonium group. Organicanionic agents are used with bioactive agents that have one or morefunctional groups having, or capable of adopting, a positive charge,such as an ammonium or guanidinium group. Organic cationic agents can beused with bioactive agents that have one or more functional groupshaving or capable of adopting a negative charge such as a carboxyl,sulfate, sulfonate, phosphate, or phosphonate group.

Organic ion agents of use in the present invention may be soluble inwater and in the organic phase to the extent required to enhance drugloading and encapsulation efficiency. In a particular embodiment,concentration of the organic ion agent in the aqueous phase ranges fromabout 0.5 to 100 mM. In another particular embodiment, the concentrationof the organic ion ranges from about 5 to 50 mM.

Biodegradable Microparticles

In certain embodiments, the controlled release composition is amicroparticle.

In certain embodiments, a bioactive agent is associated with abiodegradable polymer in a microparticle form. In a particularembodiment, a microparticle has a diameter less than 1.0 mm andtypically between 1.0 and 200.0 microns. Microparticles include bothmicrospheres and microcapsules, and may be approximately spherical orhave other geometries. Microspheres are typically approximatelyhomogeneous in composition and microcapsules comprise a core of acomposition distinct from a surrounding shell. For purposes of thisdisclosure, the terms microsphere, microparticle and microcapsule areused interchangeably.

In certain embodiments, microparticles can be made with a variety ofbiodegradable polymers. Suitable biocompatible, biodegradable polymersinclude, for example, poly(lactide)s, poly(glycolide)s,poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s,poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates,polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters,polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s,poly(alkylene alkylate)s, copolymers of polyethylene glycol andpoly(lactide)s or poly(lactide-co-glycolide)s, biodegradablepolyurethanes, blends and copolymers thereof.

In a particular embodiment, the microparticle is made ofpoly(d,l-lactide-co-glycolide) (PLGA). PLGA degrades when exposed tophysiological pH and hydrolyzes to form lactic acid and glycolic acid,which are normal byproducts of cellular metabolism. The disintegrationrate of PLGA polymers will vary depending on the polymer molecularweight, ratio of lactide to glycolide monomers in the polymer chain, andstereoregularity of the monomer subunits. Mixtures of L and Dstereoisomers that disrupt the polymer crystallinity will increasepolymer disintegration rates. In addition, microspheres may containblends of two or more biodegradable polymers, of different molecularweight and/or monomer ratio.

In other alternative embodiments, derivatized biodegradable polymers,including hydrophilic polymers attached to PLGA, can be used to formmicrospheres. In particular embodiments, the hydrophilic polymer isselected from the group consisting of, but not limited to, poly(ethyleneglycol), poly(propylene glycol) and copolymers of poly(ethylene glycol)and poly(propylene glycol).

Biodegradable Nanoparticles

In certain embodiments, the controlled release composition is ananoparticle.

In certain embodiments, the bioactive agent, with or without ahydrophilic polymer attached, is associated with biodegradable submicronparticles for controlled release of the bioactive agent. A nanoparticlehas a diameter ranging from 20.0 nanometers to about 2.0 microns and istypically between 100.0 nanometers and 1.0 micron.

Nanoparticles can be created in the same manner as microparticles,except that high-speed mixing or homogenization is used to reduce thesize of the polymer/bioactive agent emulsions to less than 2.0 micronsand typically below 1.0 micron. Alternative methods for nanoparticleproduction are known in the art and may be employed for the presentinvention.

Production of Controlled Release Compositions

Controlled release compositions of the present invention may be made byany emulsion process known in the art.

In one embodiment an organic phase, containing one or more solvents, abioactive agent and a polymer, is contacted with an aqueous phase,containing an organic ion. In a particular embodiment, the organic phaseadditionally includes a cosolvent. In another particular embodiment, theaqueous phase additionally includes an emulsifying agent.

In a particular embodiment, the organic phase is contacted with theaqueous phase to form an emulsion wherein the emulsion comprisesdroplets of the organic phase dispersed in the aqueous phase. Solvent issubsequently removed from the emulsion droplets to form hardenedmicroparticles. The hardened microparticles may then be recovered fromthe aqueous phase and dried.

In one embodiment, the organic phase may contain solvents including butnot limited to, methylene chloride, ethyl acetate, benzyl alcohol,acetone, acetic acid, propylene carbonate and other solvents in whichthe biodegradable polymer is soluble. In a particular embodiment, thesolvent of the organic phase may be selected from the group consistingof ethyl acetate and methylene chloride.

In one embodiment, the aqueous phase may contain solvents including butnot limited to, methanol, benzyl alcohol, isopropyl alcohol, water,dimethylsulfoxide, N,N-dimethylformamide, methylene chloride and othersolvents in which the bioactive agent is soluble.

In another embodiment, cosolvents may be added to the organic phase.They are optionally used to promote solubility of the bioactive agent inthe organic phase. In a particular embodiment, they are selected fromthe group consisting of, but not limited to, methyl alcohol, ethylalcohol, isopropyl alcohol, N-methyl pyrrolidinone, dimethyl sulfoxide,N,N-dimethyl formamide, PEG 200, PEG 400 and benzyl alcohol. In anotherparticular embodiment, the cosolvent may be present between about 0 and90% w/w of the solvent of the organic phase. In another particularembodiment, the cosolvent is present between about 0 and 50% w/w of thesolvent of the organic phase. The bioactive agent may be dissolved firstin an appropriate volume of the cosolvent which is then added to thesolvent of the organic phase, preferably having the biodegradablepolymer dissolved therein, so as to form a solution of all thecomponents of the organic phase. A person of ordinary skill can adjustthe volumes and order of addition to achieve the desired solution ofbioactive agent and biodegradable polymer. In a certain embodiment, thebioactive agent will be present in the organic phase at a concentrationof about 1-20% w/w. In a particular embodiment, the biodegradablepolymer will be present in the organic phase at a concentration of about240% w/w. In another particular embodiment, the biodegradable polymerwill be present in the organic phase at a concentration of about 5-20%w/w.

Organic ions are dissolved in the aqueous phase. In a certainembodiment, they are dissolved at a concentration of between about 0.1and 1000 mM. In a particular embodiment, they are dissolved at aconcentration of between about 1 to 100 mM. The concentration may beadjusted for each particular organic ion agent and bioactive agent toachieve the desired drug loading and encapsulation efficiency.

One or more emulsifying agents may be added to the aqueous phase tostabilize the emulsion. Emulsifying agents may be selected from thegroup consisting of, but not limited to, poly(vinyl alcohol), albumin,lecithin, vitamin E TPGS and polysorbates. The emulsifying agents arepresent at a concentration in the aqueous phase between 0 and 10% (w/w).In a particular embodiment, they are present at a concentration between0.5 to 5% w/w.

Pharmaceutical Formulations

In addition to the compounds formulated for parenteral administration,such as intravenous or intramuscular injection, other alternativemethods of administration of the present invention may also be used,including but not limited to intradermal administration, pulmonaryadministration, buccal administration, transdermal and transmucosaladministration. Transmucosal administration may include, but is notlimited to, ophthalmic, vaginal, rectal and intranasal. All such methodsof administration are well known in the art.

In a particular embodiment, the controlled release composition of thepresent invention may be administered intranasally, such as with nasalsolutions or sprays, aerosols or inhalants. Nasal solutions are usuallyaqueous solutions designed to be administered to the nasal passages indrops or sprays. Nasal solutions are prepared so that they are similarin many respects to nasal secretions. Thus, the aqueous nasal solutionsusually are isotonic and slightly buffered to maintain a pH of 5.5 to6.5.

Antimicrobial preservatives, similar to those used in ophthalmicpreparations, and appropriate drug stabilizers, if required, may beincluded in any of the formulations. Preservatives and other additivesmay be selected from the group consisting of, but not limited to,antimicrobials, anti-oxidants, chelating agents, inert gases and thelike. Various commercial nasal preparations are known and include, forexample, antibiotics and antihistamines and are used for asthmaprophylaxis.

In another embodiment, controlled release compositions of the presentinvention are applied topically. Such controlled release compositionsinclude, but are not limited to, lotions, ointments, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Excipients, Carriers and Diluents

Controlled release compositions of the present invention can beformulated in any excipient the biological system or entity cantolerate. Examples of such excipients include water, saline, Ringer'ssolution, dextrose solution, Hank's solution and other aqueousphysiologically balanced salt solutions. Nonaqueous vehicles, such asfixed oils, polyethylene glycol and injectable organic esters such asethyl oleate may also be used. Other useful formulations includesuspensions containing viscosity-enhancing agents, such as sodiumcarboxymethylcellulose, sorbitol or dextran.

Excipients can also contain minor amounts of additives, such assubstances that enhance isotonicity and chemical stability. Examples ofbuffers include phosphate buffer, bicarbonate buffer and Tris buffer,while examples of preservatives include thimerosol, cresols, formalinand benzyl alcohol.

Pharmaceutical carriers for controlled release compositions of thepresent invention are known to those skilled in the art. Those mosttypically utilized are likely to be standard carriers for administrationto humans including solutions such as sterile water, saline and bufferedsolutions at physiological pH.

The controlled release compositions of the present invention may besuspended in any aqueous solution or other diluent for injection in ahuman or animal patient in need of treatment. Aqueous diluent solutionsmay further include a viscosity enhancer selected from the groupconsisting of sodium carboxymethylcellulose, sucrose, mannitol,dextrose, trehalose and other biocompatible viscosity enhancing agents.The viscosity may be adjusted to a value between 2 centipoise (cp) and100 cp, preferably between 4 and 40 cp.

In a particular embodiment, a surfactant may be included in the diluentto enhance suspendability of the controlled release composition.Surfactants may be selected from the group consisting of, but notlimited to, polysorbates and other biocompatible surfactants.Surfactants are used at a concentration of between 0 and 5% (w/w),preferably between 0.1 and 1% w/w.

EXAMPLES

The following examples are included to demonstrate particularembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventors to function well in thepractice of the invention, and thus can be considered to constituteparticular modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

Example 1

Conventional Preparation of Octreotide Acetate Encapsulated inPoly(lactide-co-glycolide) (PLGA) Microparticles Using Co-SolventsAccording to Previously Used Methods.

Octreotide acetate microparticle formulations were prepared toinvestigate the effect of different co-solvents in the organic phase.Formulations A-F, prepared using an oil-in-water emulsion/solventextraction technique, are summarized in Table 1. PLGA polymer (50:50lactide/glycolide, MW 24,000,180 mg) was dissolved in ethyl acetate(EtOAc, 900 μL), and octreotide acetate (20 mg) dissolved in aco-solvent (Table 1) was added to the polymer solution. The resultinghomogeneous organic phase was added to an aqueous phase (2 mL)containing 1% poly(vinyl alcohol) (PVA) and the mixture was vortexed for15-30 seconds. The emulsion was poured into a solvent extractionsolution (10 mM sodium phosphate, pH 8.0, 150 mL) and stirred for fourhours to extract EtOAc. Particles were isolated by filtration, washedwith water and air dried overnight. The formulations were characterizedby particle size, scanning electron microscopy (SEM), morphology,octreotide core load and in vitro release profiles.

Formulation D was repeated using an emulsifying device, such as thatdisclosed in PCT Application Serial No. PCT/US04/11485, that combined ahomogeneous organic phase (2 mL) consisting of octreotide acetate (20mg), MeOH (100 μL), PLGA polymer (50:50 lactide/glycolide, MW 24,000,180 mg) and EtOAc (1.9 mL) with a 1% PVA aqueous phase (4 mL). Theemulsion was then added to a solvent extraction solution and stirred forfour hours to extract EtOAc. This process produced formulation D2 (Table1).

The co-solvents investigated had a small influence on particle size andcore load. Particle sizes were larger with the higher viscositypoly(ethylene glycol) (PEG) co-solvents. In contrast, core loads weresimilar for the methanol (MeOH) and PEG co-solvents (formulations A-C).The highest core loads were obtained for the MeOH cosolvent with a pH 8buffered emulsion step (formulation D2) and for the dimethyl sulfoxide(DMSO) cosolvent (formulation F).

In vitro release kinetics were measured in either phosphate bufferedsaline (PBS, pH 7.2, 37° C.) or 100 mM sodium acetate (NaOAc, pH 4.0,37° C.). An example is shown in Table 2 (Formulation D2). The PEGco-solvent systems showed the highest initial peptide burst (8-10%),while the remaining formulations had an initial burst in the range of2-3%. All the formulations released peptide for at least 6 weeks. Therewas a decrease in the relative release rates for formulations preparedwith polar aprotic solvents (formulations E-F) resulting in lower totalrelease of peptide relative to the other formulations.

Octreotide acetate as the free peptide was measured to be 95% intact byhigh-pressure liquid chromatography (HPLC) following incubation in therelease medium (PBS, pH 7.2, 37° C.) after 49 days. In contrast,incubation of octreotide acetate PLGA microparticle formulationsproduced 55% of modified peptide species after 70 days in the releasemedium (PBS, pH 7.2, 37° C., Table 2). HPLC analysis showed that the newpeptide entities were more hydrophobic than native octreotide acetate.HPLC/MS analysis revealed masses consistent with acylation of the parentpeptide by PLGA polymer. The masses found were consistent with randomacylation, for example, peptide plus one or two glycolic or lactic acidmonomers in any combination. It may be that acylation products arisefrom attack on PLGA fragments or the polymer backbone by nucleophilicmoieties in octreotide. At a lower pH these moieties likely would beprotonated reducing their nucleophilicity and consequently the amount ofacylated product. It was observed that formation of acylated byproductsfor octreotide acetate PLGA microparticles incubated in 100 mM sodiumacetate (NaOAc, pH 4.0) buffer was reduced to 1.25% at 49 days, inmarked contrast to the results for PBS buffer (55%). TABLE 1 OctreotideAcetate Encapsulation in PLGA Microparticles. Total Co-solventComposition Median Core load Peptide in organic of Aqueous particle(encaps. Burst Release phase Phase size eff.) (%) (Acylated) A PEG₂₀₀ 1%PVA 49 μm 2.83% 7.96 72.6% (100 μL)   (28%)   (44%) B PEG₄₀₀ 1% PVA 76μm 3.20% 10.4 63.0% (100 μL)   (32%)   (48%) C MeOH 1% PVA 25 μm 2.75%2.91 65.7% (50 μL)   (28%)   (50%) D MeOH 1% PVA + 10 34 μm 5.57% 2.5865.1% (100 μL) mM PO₄   (56%)   (50%) (pH8) D2 MeOH 1% PVA + 10 60 μm5.66% 1.90 85.8% (100 μL) mM PO₄   (57%)   (55%) (pH8) E DMF 1% PVA 38μm 3.41% 1.97 50.3% (100 μL)   (34%)   (33%) F DMSO 1% PVA 38 μm 4.88%2.74 43.4% (100 μL)   (49%)   (36%)

TABLE 2 In vitro release of formulations D2 and AG. NaOAc buffercontains 100 mM NaOAc (pH 4.0), 0.02% Tween-20 and 0.05% NaN₃. PBS isphosphate buffered saline (pH 7.2) containing 0.02% Tween-20 and 0.05%NaN₃. Samples were incubated in a shaking (150 Hz) water bath incubatorat 37 C. Peptide and acylated peptide release values are listed ascumulative percent released. % Peptide Day Released

cylated Peptide Released Formulation D2 100 mM NaOAc (pH 4)  0 0.0 0.0 1 5.55 0.15  3 13.75 0.78  6 53.47 4.11 10 71.74 5.16 14 72.19 5.26 2072.21 5.28 24 72.22 5.30 29 72.22 5.30 34 72.22 5.30 42 72.22 5.30 4872.22 5.30 Formulation D2 PBS (pH 7)  0 0.0 0.0  1 1.81 0.08  3 3.090.22  6 4.87 0.59 10 7.54 1.98 14 10.42 4.29 20 17.81 10.51 24 20.6914.06 29 23.86 18.86 34 26.21 23.12 42 32.91 28.73 48 35.13 32.14 5736.50 35.10 64 37.83 37.41 71 38.42 45.82 78 38.58 46.37 85 38.64 46.70

Formulation AG PBS (pH 7) % Peptide Day Released

cylated Peptide Released 0 0.0 0.0 1 8.04 0.33 2 9.09 0.47 6 12.27 0.6515 17.75 1.23 24 20.03 1.78 29 23.78 2.66 35 36.16 5.62 42 43.80 8.15 4951.17 11.13 57 61.47 15.57 64 67.63 18.16

Example 2

Production of Water Insoluble Organic Acid Salts (Complexes) ofOctreotide and Encapsulation in PLGA Microparticles According toPreviously Used Methods.

Organic ion agents were investigated where the organic ion was initiallycomplexed with octreotide acetate to form a water insoluble saltfollowed by encapsulation in PLGA microparticles.

Sodium Dodecylsulfate (SDS). An octreotide-SDS complex was prepared bydissolving octreotide acetate (100 mg) in H₂O (500 μL). SDS (1.5 equiv,43.2 mg) dissolved in H₂O (500 μL) was added drop wise to the octreotideacetate solution with vortexing at room temperature. A precipitateimmediately formed. The sample was centrifuged at 10,000 rpm for 1minute and the supernatant removed by pipette. The precipitate waswashed with cold water and lyophilized providing an octreotide-SDScomplex (95.3 mg). RP-HPLC analysis showed a pronounced broadening ofthe octreotide peak indicating formation of the octreotide/SDS complex.Formulations G-I were prepared using an oil-in-water emulsion/solventextraction technique. PLGA polymer (MW 24,000, 180 mg) was dissolved inEtOAc (900 μL). Octreotide/SDS complex was dissolved in MeOH (100 μL)and added to the polymer solution. This resulted in a heterogeneousorganic phase. In the case of formulation I (Table 3) an additionalaliquot of MeOH (100 μL) was added to produce a homogeneous organicphase. The resulting organic phase was added to an aqueous phase (2 mL)containing 1% PVA and the mixture was vortexed for 15-30 seconds. Theemulsion was poured into a solvent extraction solution (10 mM sodiumphosphate, pH 8.0, 150 mL) and stirred for four hours to extract EtOAc.Particles were isolated by filtration, washed with water and air driedovernight. The formulations were characterized by particle size, SEMmorphology, octreotide core load and in vitro release profiles.

The measured core load for formulations G-I prepared from theoctreotide-SDS complex were relatively low, between 0.6-2.6% (Table 3).Also the median particle size was reduced by approximately 40% relativeto formulations (A-F) prepared with octreotide acetate.

The in vitro release profiles of formulations G-I in PBS were quitesimilar. Each had an initial burst of approximately 20% followed bythree weeks of 1.5% release/week. After three weeks the rate of releaseincreased to approximately 7.0% release/week, culminating inapproximately 80% total peptide release at 9 weeks.

The in vitro PBS release assay with these formulations resulted in therelease of similar amounts of acylated (40-55%) and total peptidecompared to octreotide acetate (formulations A-F). TABLE 3Octreotide-SDS Complex in the Organic Phase. Median Co-solvent inparticle Core load Burst Formulation Organic Phase size (encaps. eff.)(Acylated) G MeOH (100 μL) 11.4 μm 0.61% 20.3% (6.1%) (49%) H MeOH (100μL) 12.4 μm 0.75% 21.2% (7.5%) (40%) I MeOH (200 μL) 12.9 μm 2.64% 20.2%(2.6%) (42%)

Benzoic Acid. Formulations (J-M) were prepared using one to tenequivalents of benzoic acid co-dissolved in the organic phase with PLGA.PLGA polymer (MW 24,000,180 mg) and benzoic acid (2.4-24 mg) weredissolved in EtOAc (900 μL). Octreotide acetate was dissolved in MeOH(100 μL) and added to the polymer solution yielding a homogeneousorganic phase. The resulting organic phase was added to an aqueous phase(2 mL) containing 1% PVA and the mixture was vortexed for 15-30 seconds.The emulsion was poured into a solvent extraction solution (10 mM sodiumphosphate, pH 8.0, 150 mL) and stirred for four hours to extract EtOAc.Particles were isolated by filtration, washed with water and air driedovernight. The core loads measured between 0.88-1.67% over the range of1-10 added equivalents of benzoic acid per equivalent of octreotideacetate (Table 4).

Pamoic Acid. An octreotide-pamoate complex was prepared by dissolvingpamoic acid (19.4 mg, 0.05 mmol) in 0.2 N NaOH (500 μL) to provide thesodium pamoate salt. Octreotide acetate (100 mg, 0.10 mmol) wasdissolved in deionized water (100 μL) and added drop wise with gentlevortexing to the sodium pamoate salt solution. This produced aflocculent light yellow precipitate. The precipitate was pelleted bycentrifugation, and the supernatant removed by pipette. The pellet waswashed with water (1.0 mL), re-suspended in water and lyophilized to alight yellow powder (113 mg). The octreotide/pamoate ratio of thispreparation was 1.71 as measured by RP-HPLC.

A second octreotide-pamoate complex was prepared by dissolving pamoicacid (19.4 mg, 0.05 mmol) in 0.4 N NaOH (250 μL) and dioxane (250 μL) toprovide a solution of sodium pamoate in dioxane/water (1:1). Octreotideacetate (50 mg, 0.05 mmol) was dissolved in dioxane/water (1:1, 200 μL).The octreotide acetate solution was added drop wise to the sodiumpamoate with mixing to provide a light yellow, homogenous solution. Thismaterial was lyophilized to dryness providing a light yellow powder (65mg). The octreotide/pamoate ratio of this preparation was 1.02 asmeasured by RP-HPLC. These two preparations were used to prepare newPLGA microparticle formulations. TABLE 4 Benzoic Acid and OctreotideAcetate in Organic Phase. Benzoic Median Core load Co-solvent inacid:Octreotide particle (encaps. Formulation Organic Phase acetateratio size eff.) J MeOH (100 μL) 1 21.8 μm 1.36% (14%) K MeOH (100 μL) 219.5 μm 0.88% (8.8%)  L MeOH (100 μL) 5 18.8 μm 1.61% (16%) M MeOH (100μL) 10 17.9 μm 1.67% (17%)

Microparticle formulations (Table 5, Q-W) were prepared by anoil-in-water emulsion/solvent extraction method. PLGA polymer (MW24,000, 180 mg) was dissolved in EtOAc (1000 μL). Octreotide pamoate (20or 40 mg) was dissolved in benzyl alcohol (BnOH, 1000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase in a ratio of 1:2to provide an emulsion. The emulsion was collected directly into a 0.3%PVA solvent extraction solution (150 mL) and stirred for four hours toextract EtOAc. Hardened microparticles were collected by filtration,washed with water, air dried and stored at 4° C.

Formulation characterization (Table 5) revealed that the initialoctreotide/pamoate ratio of 1.7 had little effect on the encapsulationefficiency and core load relative to the formulations prepared with theoctreotide/pamoate ratio of 1.02. In contrast, changing the co-solventto benzyl alcohol increased the encapsulation efficiency byapproximately 60% relative to methanol (e.g. Formulation S compared toT).

The in vitro release profiles of these formulations in PBS demonstratedtotal peptide released (79-92%, Table 5 Q-T) is comparable to PLGAoctreotide acetate microparticles made by conventional methods(formulations D, F, Table 1) while the amount of acylated peptidereleased (28-40%, Table 5 Q-T) is decreased slightly relative toconventional formulations (44-55%, Table 1, A-D).

Formulations prepared using the octreotide/pamoate ratio of 1:1 did notshow as strong a dependence of encapsulation efficiency and core load onthe nature of the co-solvent as the 1.7 ratio formulations above. Thedifferences in solubility for the complexes with differentoctreotide/pamoate ratios in the co-solvent is proposed as anexplanation for this observation. The higher octreotide/pamoate ratiomaterial had an increased solubility in benzyl alcohol relative tomethanol resulting in higher encapsulation efficiency. In contrast, itwas found that there was no significant difference in solubility inmethanol versus benzyl alcohol for the 1:1 octreotide/pamoate complex.This resulted in similar encapsulation efficiencies and core loadsindependent of the co-solvents.

The in vitro release profiles of these 1:1 formulations (U-W) revealsimilar trends as discussed above, namely, that the total percent ofpeptide released (85-110%, Table 5 U-W) is again comparable toconventional formulations (Example 1) (ca. 85%, Table 2) while theamount of acylated product released (35-44% Table 5 U-W) is decreasedsomewhat relative to conventional formulations (44-55%, Table 1, A-D2).

Analysis of the final octreotide/pamoate molar ratio showed a widevariation among the formulations tested (Table 5) with a range from2.1:1 (formulation W) to over 200:1 (formulation R). In all cases theratio is more than twice the octreotide/pamoate ratio of the startingpeptide salt complex. Thus the use of a preformed pamoate salt of thepeptide octreotide yielded highly variable octreotide/pamoate molarratios in the final sustained release formulation. TABLE 5Octreotide-Pamoate Microparticles Prepared Using Pre-Formed Complex.Octreotide/ pamoate ratio Median Core Total Peptide initial Co-solventin particle load (encap Release Formulation (final) Organic Phase sizeeff) (Acylated) Q 1.7:1 MeOH (100 μL) 40 μm 6.52% 88.6% (4.4:1)   (65%)(28.1%) R 1.7:1 MeOH (500 μL) 34 μm 3.34% 79.2% (201:1)   (33%) (38.9%)S 1.7:1 BnOH (200 μL) 31 μm 8.29% 87.2% (13:1)   (83%) (39.7%) T 1.7:1MeOH (200 μL) 37 μm 5.03% 91.5% (21:1)   (50%) (32.2%) U 1:1 MeOH (200μL) 48 μm 4.93% 92.3% (5.3:1)   (49%) (37.3%) V 1:1 BnOH (200 μL) 48 μm4.76%  110% (5.4:1)   (48%) (44.4%) W 1:1 BnOH (200 μL) 44 μm 5.01%84.9% (2.1:1)   (25%) (35.0%)

Example 3

Octreotide Acetate Encapsulation in PLGA Microspheres Using Organic AcidSalts in the Aqueous Emulsion Phase According to the Present Invention.

Surprisingly it was discovered that the use of an organic acid salt inthe aqueous phase of the emulsification process allowed use of a watersoluble peptide and eliminated the need to prepare complexed species inan independent step prior to preparing the formulation. The presentinvention provided added benefits such as increased drug coreload,consistent octreotide/organic ion ratio, and decreased peptidedegradation during in vitro release.

Microparticle formulations were prepared by an oil-in-wateremulsion/solvent extraction method. PLGA polymer (MW 24,000, 140-180 mg)was dissolved in EtOAc (1000 μL). Octreotide acetate (20-60 mg) wasdissolved in BnOH (1000 μL) and added to the polymer solution yielding ahomogenous organic phase. The resulting organic phase was combined witha 1% PVA aqueous phase containing 10-50 mM disodium pamoate to providean emulsion. The emulsion was collected directly into a 0.3% PVA solventextraction solution (150 mL) and stirred for four hours to extractEtOAc. Hardened microparticles were collected by filtration, washed withwater, air dried and stored at 4° C. This resulted in a finaloctreotide/pamoate ratio of approximately 1-1.5 in the microparticleformulation measured by RP-HPLC (Table 6).

The effects of various experimental parameters on core load wereinvestigated including organic to aqueous phase ratio, nature ofco-solvent, and volume of co-solvent. BnOH was found to be a moresuitable co-solvent than MeOH. It was possible to use BnOH in largervolumes than MeOH, as MeOH induced polymer precipitation in the organicphase. BnOH also led to a small increase in core load versus MeOH(Formulation Y, AB, Table 6). However, the use of BnOH without theorganic ion in the aqueous phase did not provide high core loads orencapsulation efficiencies (AI, Table 6). It was also found thatdecreasing the organic to aqueous phase ratio increased theencapsulation efficiency slightly when BnOH was used as the co-solvent(Formulations AE, AF, Table 6). In all cases the molar ratio ofoctreotide to pamoate was tightly grouped between about 1.0 and 1.5, incontrast to the formulations of Example 2 (Table 5) where the use of apreformed octreotide/pamoate complex led to wide variations of the finaloctreotide/pamoate ratio from 2.1 to over 200.

Significantly, product with predictable and elevated drug core loadsranging from 5-17.5% could be formed with the method of the presentinvention, (formulations AD, AG, AH, Table 6), in contrast to the priorart methods of Examples 1 and 2 where the maximum drug core loadachieved was about 8% (Table 5-S) with averages ranging from 2-6%(Tables 1-5). In addition, the compositions of the present inventionhave consistent stoichiometry for the molar ratio of bioactive agent toorganic ion (Table 6). This is in contrast to the compositions madeusing previous methods (Table 5). Furthermore, the relative productionof acylated peptide is lower for microparticles made with the organicion in the aqueous phase (Table 6) than for microparticles made with theuse of preformed octreotide-pamoate (Table 5) or octreotide acetate(Table 2). TABLE 6 Octreotide-Pamoate Complex Microparticles by an insitu Process. Formulation Organic/ Total (Octreotide/ Octreotide AqueousPeptide pamoate final acetate phase Median particle Core load Releaseratio) input Co-solvent ratio size (encap eff) (Acylated) X 40 mg MeOH1:4 79 μm 8.52% 98.8% (1.09:1)  (200 μL) (46.8%) (15.7%) Y 20 mg MeOH 1:10 71 μm 5.13%  120% (0.86:1)  (200 μL)   (51%) (30.6%) Z 20 mg BnOH1:2 44 μm 7.61% 97.1% (1.09:1) (1000 μL)   (76%) (4.11%) AA 20 mg BnOH1:2 59 μm 6.79%  101% (1.01:1) (1000 μL)  (6.8%) (12.7%) AB 20 mg BnOH1:2 45 μm 6.19% 97.1% (1.11:1)  (500 μL)   (62%) (14.8%) AC 20 mg BnOH1:2 47 μm 7.51% 96.8% (1.14:1) (1000 μL)   (75%) (13.4%) AD 40 mg BnOH1:2 53 μm 12.7%  101% (1.11:1) (1000 μL)   (64%) (16.1%) AE 60 mg BnOH1:2 45 μm 9.51%  103% (1.41:1)  (500 μL)   (32%) (26.1%) AF 60 mg BnOH1:4 50 μm 12.0%  108% (1.16:1)  (500 μL)   (40%) (21.7%) AG 60 mg BnOH1:2 39 μm 17.2% 92.5% (1.39:1) (1000 μL)   (57%) (20.7%) AH 60 mg BnOH1:2 37 μm 17.5%  111% (1.36:1) (1000 μL)   (57%) (25.0%) AI 60 mg BnOH1:2 40 μm 6.85% ND (1000 μL)   (23%)

The effect of organic acid concentration in the aqueous phase wasexplored to determine the optimal manufacturing parameters. PLGA polymer(MW 24,000, 160 mg) was dissolved in EtOAc (1000 μL). Octreotide acetate(40 mg) was dissolved in BnOH (1000 μL) and added to the polymersolution yielding a homogenous organic phase. The resulting organicphase was combined with a 1% PVA aqueous phase containing 20 or 50 mMsodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (150 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. Formulations AJ-AL show that 20 or 50 mM disodium pamoate had noeffect on core load relative to 10 mM disodium pamoate (Table 7).However, the disodium pamoate concentration in the aqueous phase didhave a measurable effect on the “day one” in vitro PBS release. Theformulation prepared using 50 mM disodium pamoate resulted in a 15%burst (Formulation AL, Table 7) as compared to less than 4% burst forformulations prepared with 20 mM organic ion (Formulations AJ, AK, Table7). This suggests that excess organic ion in the aqueous phase isdeleterious to the in vitro release performance of the formulations.TABLE 7 The effect of organic ion concentration on the formation ofoctreotide-pamoate microparticles. Formulation Organic/ Total(Octreotide/ Sodium Aqueous Core load Peptide pamoate pamoate phaseMedian particle (encap PBS Burst Release final ratio) conc ratio sizeeff) Release (Acylated) AJ 20 mM 1:1 33 μm 13.3% 3.77%  108% (1.33:1)  (67%) (25.7%) AK 20 mM 1:2 41 μm 13.3% 3.38%  106% (1.29:1)   (67%)(22.4%) AL 50 mM 1:2 54 μm 12.8% 15.0%  110% (1.29:1)   (64%) (26.8%)

Alternative organic ions in addition to pamoate were investigated toexplore the general utility of the present invention. Microparticleformulations were prepared by an oil-in-water emulsion/solventextraction method. PLGA polymer (MW 24,000, 160 mg) was dissolved inEtOAc (1000 μL). Octreotide acetate (40 mg) was dissolved in BnOH (1000μL) and added to the polymer solution yielding a homogenous organicphase. The resulting organic phase was combined with a 1% PVA aqueousphase containing 10-20 mM organic acid as its sodium salt to provide anemulsion. The emulsion was collected directly into a 0.3% PVA solventextraction solution (150 mL) and stirred for four hours to extractEtOAc. Hardened microparticles were collected by filtration, washed withwater, air dried and stored at 4° C. This resulted in microparticleformulations with octreotide core loads between 6.8 and 15.3% asmeasured by RP-HPLC (Table 8). The effects of the tested organic ions oncore load are revealing. Formulations AM-AP show no increase in themeasured core load relative to control containing sodium pamoate(Formulations AT, AU, AY, Table 8). In contrast formulations AQ-AS,AV-AX and AZ-BB, which employed organic acids ranging from cholic acidto bicyclic aromatics, provided peptide core loads comparable to pamoicacid (Table 8). These results imply that organic acids with appropriatephysiochemical properties can be substituted for pamoic acid to producecomparable microparticle formulations. TABLE 8 The effect of variousorganic acids (sodium salts) in the aqueous phase on the formation ofoctreotide-complex microparticles. Particle Core load Total PeptideFormulation Organic acid sodium salt (conc.) size (encap eff) Release(Acylated) AM Succinic (10 mM) 34.1 μm   7.74% 99.9%  (39%) (53.4%) ANBenzoic (10 mM) 32 μm 6.88% 105% (34%) (56.7%) AO Salicylic (10 mM) 34μm 7.78% 106% (39%) (54.0%) AP Trifluoromethyl-p-toluic (10 mM) 33 μm8.92% 107% (45%) (50.7%) AQ Cholic (20 mM) 60 μm 13.2% 104% (66%)(47.2%) AR 2-Naphthalene sulfonic (20 mM) 38 μm 11.6% 110% (58%) (42.6%)AS 2,3-Naphthalene dicarboxylic (10 mM) 38 μm 13.1% 109% (66%)   (47%)AT Pamoic (10 mM) 45 μm 13.8 98.5%  (69%)   (37%) AU Pamoic (10 mM) 43μm 14.2% 97.5%  (71%)   (31%) AV 1-Hydroxy-2-naphthoic (20 mM) 42 μm15.3% 152% (76%) (25.7%) AW 3-Hydroxy-2-naphthoic (20 mM) 40 μm 14.6%105% (72%) (20.8%) AX 2-Naphthoic (20 mM) 39 μm 13.4% 134% (67%) (32.9%)AY Pamoic (10 mM) 46 μm 14.4% 103% (72%)   (22%) AZ 2-Naphthalenesulfonic (20 mM) 36 μm 10.8% 138% (54%) (33.0%) BA 2,3-Naphthalenedicarboxylic 46 μm 12.1% 97.8%  (10 mM) (61%)   (25%) BBSalicylsalicylic (20 mM) 39 μm 12.4% 114% (62%) (23.2%)

Example 4

Encapsulation of Additional Peptides in PLGA Microspheres Using OrganicAcid Salts in the Aqueous Emulsion Phase According to the PresentInvention.

Oxytocin acetate and leuprolide acetate were formulated in PLGAmicroparticles according to the present invention as described in theexamples below. The results of these investigations demonstrate theutility of the present invention in relation to increased core load andencapsulation efficiency (Formulations BI vs BJ-BK and BLvs BM) relativeto conventional methodology (Table 9).

Formulation BI (Leuprolide)—Conventional Encapsulation Method

PLGA polymer (MW 24,000, 160 mg) was dissolved in CH₂Cl₂ (1000 μL).Leuprolide acetate (40 mg) was dissolved in BnOH (1000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase to provide anemulsion. The emulsion was collected directly into a 0.3% PVA solventextraction solution (150 mL) and stirred for four hours to extractEtOAc. Hardened microparticles were collected by filtration, washed withwater, air dried and stored at 4° C. This provided formulation BI (140mg, 70.0% yield) with a median particle size 50.1 μm. The core load(1.99%), encapsulation efficiency (9.95%) and in vitro burst (1.63%)were determined by RP-HPLC assay.

Formulation BJ (Leuprolide)—Organic Ion Assisted Encapsulation Method

PLGA polymer (MW 24,000, 160 mg) was dissolved in CH₂Cl₂ (1000 μL).Leuprolide acetate (40 mg) was dissolved in BnOH (1000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (100 mL) andstirred for 10 minutes. A secondary extraction solution consisting of 2%isopropanol (200 mL) was added and stirred for an additional four hours.Hardened microparticles were collected by filtration, washed with water,air dried and stored at 4° C. This provided formulation BJ (157 mg,78.5% yield) with a median particle size 54.0 μm. The core load (9.4%),encapsulation efficiency (47.0%) and in vitro burst (5.31%) weredetermined by RP-HPLC assay.

Formulation BK (Leuprolide)—Organic Ion Assisted Method

A microparticle formulation was prepared by an oil-in-wateremulsion/solvent extraction method. PLGA polymer (MW 24,000, 160 mg) wasdissolved in CH₂Cl₂ (1000 μL). Leuprolide acetate (40 mg) was dissolvedin BnOH (1000 μL) and added to the polymer solution yielding ahomogeneous organic phase. The resulting organic phase was combined witha 1% PVA aqueous phase containing 50 mM disodium pamoate to provide anemulsion. The emulsion was collected directly into a 0.3% PVA solventextraction solution (100 mL) and stirred for 10 minutes. A secondaryextraction solution consisting of 2% isopropanol (200 mL) was added andstirred for an additional four hours. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BK (120 mg, 60.0% yield) with a medianparticle size 43.1 μm. The core load (10.6%), encapsulation efficiency(53.0%) and in vitro burst (21.1%) were determined by RP-HPLC assay.

Formulation BL (Oxytocin)—Conventional Encapsulation Method

PLGA polymer (MW 13,000, 180 mg) was dissolved in EtOAc (900 μL).Oxytocin acetate (20 mg) was dissolved in MeOH (100 μL) and added to thepolymer solution yielding a milky suspension as the organic phase. Theresulting organic phase was combined with a 1% PVA aqueous phasecontaining 5% EtOAc to provide an emulsion. The emulsion was collecteddirectly into a 10 mM sodium phosphate (pH 8, 0° C., 150 mL) solventextraction solution and stirred for four hours while warming to roomtemperature to extract EtOAc. Hardened microparticles were collected byfiltration, washed with water, air dried and stored at 4° C. Thisprovided formulation BL (143 mg, 71.5% yield) with a median particlesize 44.0 μm. The core load (1.67%), encapsulation efficiency (16.7%)and in vitro burst (46.3%) were determined by RP-HPLC assay.

Formulation BM (Oxytocin)—Organic Ion Assisted Encapsulation Method

PLGA polymer (MW 24,000, 180 mg) was dissolved in EtOAc (1800 μL).Oxytocin acetate (40 mg) was dissolved in MeOH (200 μL) and added to thepolymer solution yielding a milky suspension as the organic phase. Theresulting organic phase was combined with a 1% PVA aqueous phasecontaining 10 mM disodium pamoate to provide an emulsion. The emulsionwas collected directly into a 0.3% PVA solvent extraction solution (150mL) and stirred for four hours to extract EtOAc. Hardened microparticleswere collected by filtration, washed with water, air dried and stored at4° C. This provided formulation BM (158 mg, 79.0% yield) with a medianparticle size 144 μm. The core load (8.9%), encapsulation efficiency(44.5%) and in vitro burst (21.1%) were determined by RP-HPLC assay.TABLE 9 Peptide-pamoate complex microparticles by an in situ process.Pamoate Formulation Peptide conc. Core load Encap. Eff. BI leuprolide  0mM 2.0% 10.0% BJ leuprolide 10 mM 9.4% 47.0% BK leuprolide 50 mM 10.6%53.0% BL oxytocin  0 mM 1.7% 16.7% BM oxytocin 10 mM 8.9% 49.1%

Example 5

Insulin Encapsulation in PLGA Microparticles Using Organic Acid Salts inthe Aqueous Emulsion Phase.

Sodium Dodecylsulfate Microparticle formulations were prepared using anoil-in-water emulsion/solvent extraction method. The organic phaseconsisted of PLGA polymer (MW 11,800, 150 mg) and PEGylated-insulin (50mg) dissolved in CH₂Cl₂(2 mL). The aqueous phase consisted of 1% PVA and14 mM SDS. The homogeneous organic and aqueous phases were combined in aratio of 1:5 to produce an organic in aqueous phase emulsion. Theemulsion was collected directly into a 0.3% PVA solvent extractionsolution (100 mL) and stirred for 10 minutes before adding 100 mL 2%IPA. The solvent extraction solution was then stirred for an additional3 hours to extract CH₂Cl₂. Hardened microparticles were collected byfiltration, washed with water, air dried and stored at −20° C. Theresulting microparticle had a core load of 21% (encapsulation efficiency84%). These microparticles were characterized by a large in vitro burstof 50% at 24 h in PBS at 37° C.

Disodium Pamoate Microparticle formulations were prepared using anoil-in-water emulsion/solvent extraction method. The organic phaseconsisted of PLGA polymer (MW 11,800, 75 mg) and PEGylated-insulin (25mg) dissolved in CH₂Cl₂ (1 mL). The aqueous phase consisted of 1% PVAand 10 mM disodium pamoate. The homogeneous organic and aqueous phaseswere combined in a ratio of 1:5 to produce an organic in aqueous phaseemulsion. The emulsion was collected directly into a 0.3% PVA solventextraction solution (50 mL) and stirred for 10 minutes before addingwater (100 mL). The solvent extraction solution was then stirred for anadditional 3 hours to extract CH₂Cl₂. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at −20°C. The resulting microparticles had a core load of 18% (encapsulationefficiency 78%) and a final PEGylated-insulin/pamoate ratio of 1:2. Incontrast to the microparticles made with SDS, these microparticles had alow in vitro burst of 5% in PBS at 37° C.

Example 6

Evaluation of the Pharmacokinetics of Octreotide in PLGA Microparticlesafter Administration to Sprague Dawley Rats.

Blood serum levels were measured for octreotide released from PLGAmicroparticle formulations injected subcutaneously in rats. Animals(n=6/group) were treated once by subcutaneous injection of a single doselevel (˜8-10 mg/kg) of six different octreotide PLGA microparticleformulations. At hours 1 and 6, and on days 1, 4, 7, 11, 14, 20, 28, 42and 54, serum samples were obtained from each animal to evaluate theoctreotide pharmacokinetics. Serum concentrations were measured by acommercially available extraction-free radioimmunoassay kit (#S-2211)(Peninsula Labs). The Limit of Quantitation (LOQ) of the assay was 0.1ng/mL. The mean octreotide serum concentrations for each time point arereported in Table 10. The preparation of the octreotide PLGAformulations tested is described below. TABLE 10 Mean octreotide serumlevels (ng/mL) after a single subcutaneous treatment in rats. DoseSample Day Formulation (mg/Kg) 0 0.04 0.25 1 4 7 11 14 20 28 42 54 BC10.2 0.00 39.75 3.83 0.62 1.44 3.07 3.71 3.42 3.51 1.95 0.39 0.00 BD 8.90.00 39.95 4.00 0.95 1.66 3.41 3.64 3.44 2.03 1.04 0.45 0.00 BE 9.7 0.0036.35 4.09 2.04 2.13 2.59 2.89 2.94 2.19 1.81 3.09 0.90 BF 8.6 0.0039.75 3.89 1.33 2.54 3.06 3.16 2.89 1.43 0.64 1.52 0.00 BG 9.2 0.0029.70 3.82 2.06 1.85 2.28 1.96 2.00 1.70 0.97 2.24 1.39 BH 9.4 0.0039.80 4.13 2.90 3.70 3.64 3.54 3.44 2.34 1.70 1.63 0.05

Preparation and Characterization of Octreotide Formulations Used in theAnimal Study.

Formulation BC

PLGA polymer (MW 24,000, 720 mg) was dissolved in EtOAc (4000 μL).Octreotide acetate (80 mg) was dissolved in BnOH (4000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (600 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BC (754 mg, 94% yield) with a medianparticle size 55.0 μm. The core load (8.5%), encapsulation efficiency(85.0%) and in vitro burst (7.4%) were determined by RP-HPLC assay.

Formulation BD

PLGA polymer (MW 24,000, 680 mg) was dissolved in EtOAc (4000 μL).Octreotide acetate (120 mg) was dissolved in BnOH (4000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (600 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BD (694 mg, 94% yield) with a medianparticle size 58.7 μm. The core load (11.8%), encapsulation efficiency(78.7%) and in vitro burst (4.1%) were determined by RP-HPLC assay.

Formulation BE

PLGA polymer (MW 24,000, 680 mg) was dissolved in EtOAc (4000 μL).Octreotide acetate (120 mg) was dissolved in BnOH (4000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (600 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BE (727 mg, 91% yield) with a medianparticle size 52.2 μm. The core load (11.6%), encapsulation efficiency(77.3%) and in vitro burst (2.75%) were determined by RP-HPLC assay.

Formulation BF

PLGA polymer (MW 24,000, 640 mg) was dissolved in EtOAc (4000 μL).Octreotide acetate (160 mg) was dissolved in BnOH (4000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (600 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BF (766 mg, 95.8% yield) with a medianparticle size 47.7 μm. The core load (14.7%), encapsulation efficiency(73.5%) and in vitro burst (5.5%) were determined by RP-HPLC assay.

Formulation BG

PLGA polymer (MW 28,000, 640 mg) was dissolved in EtOAc (4000 μL).Octreotide acetate (160 mg) was dissolved in BnOH (4000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (600 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BG (715 mg, 89.3% yield) with a medianparticle size 48.7 μm. The core load (11.9%), encapsulation efficiency(59.5%) and in vitro burst (2.3%) were determined by RP-HPLC assay.

Formulation BH

PLGA polymer (MW 14,000, 560 mg) was dissolved in EtOAc (4000 μL).Octreotide acetate (240 mg) was dissolved in BnOH (4000 μL) and added tothe polymer solution yielding a homogeneous organic phase. The resultingorganic phase was combined with a 1% PVA aqueous phase containing 10 mMdisodium pamoate to provide an emulsion. The emulsion was collecteddirectly into a 0.3% PVA solvent extraction solution (600 mL) andstirred for four hours to extract EtOAc. Hardened microparticles werecollected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BH (680 mg, 85.0% yield) with a medianparticle size 40.6 μm. The core load (17.4%), encapsulation efficiency(58.0%) and in vitro burst (6.8%) were determined by RP-HPLC assay.

All of the compositions and methods disclosed and claimed herein can bemade and executed without undue experimentation in light of the presentdisclosure. While the compositions and methods of this invention havebeen described in terms of particular embodiments, it will be apparentto those of skill in the art that variations may be applied to thecompositions, and methods and in the steps or in the sequence of stepsof the methods described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents that are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope, and concept of theinvention as defined by the appended claims.

1. A composition comprising: a) a bioactive agent; b) an organic ion,wherein said organic ion protects against degradation of the polymer orbioactive agent; and c) a polymer, wherein said polymer encapsulatessaid bioactive agent and said organic ion.
 2. The composition of claim1, wherein said composition is selected from the group consisting ofmicroparticles and nanoparticles.
 3. The composition of claim 2, whereinsaid microparticles and nanoparticles are biodegradable.
 4. Thecomposition of claim 1, wherein said polymer is selected from the groupconsisting of poly(lactide)s, poly(glycolide)s,poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s,poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates,polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters,polyacetyls, polycyanoacrylates, polyetheresters, poly(dioxanone)s,poly(alkylene alkylate)s, copolymers of polyethylene glycol andpolyorthoester, biodegradable polyurethanes, blends and copolymersthereof.
 5. The composition of claim 1, wherein said bioactive agent isselected from the group consisting of proteins, nucleic acids,carbohydrates, peptides, LHRH agonists and synthetic analogs thereof,leuprolide, oxytocin, somatostatin and synthetic analogs thereof, smallmolecule pharmaceutical substances, immunogens, metabolic precursorscapable of promoting growth and survival of cells and tissues,antineoplastic agents, hormones, antihistamines, cardiovascular agents,anti-ulcer agents, bronchodilators, vasodilators, central nervous systemagents and narcotic antagonists.
 6. The composition of claim 1, whereinsaid organic ion is selected from the group consisting of pamoate,trifluoromethyl-p-toluate, cholate, 2-naphthalene sulfonate,2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate,3-hydroxy-2-naphthoate, 2-naphthoate, and salicylsalicylate.
 7. Thecomposition of claim 1, wherein the stoichiometry of the bioactive agentrelative to the organic ion ranges from about 1.0 to 1.5.
 8. Thecomposition of claim 1, wherein the bioactive agent is selected from thegroup consisting of octreotide, octreotide acetate and pharmaceuticalequivalents thereof and the organic ion is pamoate.
 9. The compositionof claim 1, wherein the organic ion interacts with the bioactive agentto form a charged or neutral complex.
 10. A controlled releasemicroparticle composition comprising a bioactive agent in a polymerproduced through a process which comprises the steps of: a) combining abiodegradable polymer and an organic phase; b) combining a bioactiveagent and said organic phase; c) combining an organic ion and an aqueousphase; d) contacting the organic and aqueous phases through the use ofan emulsion process; and e) recovering said microparticles to produce acontrolled release composition.
 11. The composition of claim 10, whereinsaid composition is selected from the group consisting of microparticlesand nanoparticles.
 12. The composition of claim 11, wherein saidmicroparticles and nanoparticles are biodegradable.
 13. The compositionof claim 10, wherein said polymer is selected from the group consistingof poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s,poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolicacid)s, polycaprolactone, polycarbonates, polyesteramides,polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls,polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylenealkylate)s, copolymers of polyethylene glycol and polyorthoester,biodegradable polyurethanes, blends and copolymers thereof.
 14. Thecomposition of claim 10, wherein said bioactive agent is selected fromthe group consisting of proteins, nucleic acids, carbohydrates,peptides, LHRH agonists and synthetic analogs thereof, leuprolide,oxytocin, somatostatin and synthetic analogs thereof, small moleculepharmaceutical substances, immunogens, metabolic precursors capable ofpromoting growth and survival of cells and tissues, antineoplasticagents, hormones, antihistamines, cardiovascular agents, anti-ulceragents, bronchodilators, vasodilators, central nervous system agents andnarcotic antagonists.
 15. The composition of claim 10, wherein saidorganic ion is selected from the group consisting of pamoate,trifluoromethyl-p-toluate, cholate, 2-naphthalene sulfonate,2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate,3-hydroxy-2-naphthoate, 2-naphthoate, and salicylsalicylate.
 16. Thecomposition of claim 10, wherein the stoichiometry of the bioactiveagent relative to the organic ion ranges from about 1.0 to 1.5.
 17. Thecomposition of claim 10, wherein the bioactive agent is selected fromthe group consisting of octreotide, octreotide acetate andpharmaceutical equivalents thereof and the organic ion is pamoate. 18.The composition of claim 10, wherein the organic ion interacts with thebioactive agent to form a charged or neutral complex.
 19. A compositioncomprising: a) a bioactive agent; b) an organic ion; and c) a polymer,wherein said polymer encapsulates said bioactive agent and said organicion, wherein a core load of said bioactive agent is greater than about9%.
 20. The composition of claim 19, wherein said composition isselected from the group consisting of microparticles and nanoparticles.21. The composition of claim 20, wherein said microparticles andnanoparticles are biodegradable.
 22. The composition of claim 19,wherein said polymer is selected from the group consisting ofpoly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s,poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolicacid)s, polycaprolactone, polycarbonates, polyesteramides,polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls,polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylenealkylate)s, copolymers of polyethylene glycol and polyorthoester,biodegradable polyurethanes, blends and copolymers thereof.
 23. Thecomposition of claim 19, wherein said bioactive agent is selected fromthe group consisting of proteins, nucleic acids, carbohydrates,peptides, LHRH agonists and synthetic analogs thereof, leuprolide,oxytocin, somatostatin and synthetic analogs thereof, small moleculepharmaceutical substances, immunogens, metabolic precursors capable ofpromoting growth and survival of cells and tissues, antineoplasticagents, hormones, antihistamines, cardiovascular agents, anti-ulceragents, bronchodilators, vasodilators, central nervous system agents andnarcotic antagonists.
 24. The composition of claim 19, wherein saidorganic ion is selected from the group consisting of pamoate,trifluoromethyl-p-toluate, cholate, 2-naphthalene sulfonate,2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate,3-hydroxy-2-naphthoate, 2-naphthoate, and salicylsalicylate.
 25. Thecomposition of claim 19, wherein the stoichiometry of the bioactiveagent relative to the organic ion ranges from about 1.0 to 1.5.
 26. Thecomposition of claim 19, wherein the bioactive agent is selected fromthe group consisting of octreotide, octreotide acetate andpharmaceutical equivalents thereof and the organic ion is pamoate. 27.The composition of claim 19, wherein the organic ion interacts with thebioactive agent to form a charged or neutral complex.
 28. A compositioncomprising: a) a bioactive agent; b) an organic ion; and c) a polymer,wherein said polymer encapsulates said bioactive agent and said organicion, wherein less than about 25% of said bioactive agent is in adegraded form upon release of said bioactive agent into a physiologicalmedium.
 29. The composition of claim 28, wherein said composition isselected from the group consisting of microparticles and nanoparticles.30. The composition of claim 29, wherein said microparticles andnanoparticles are biodegradable.
 31. The composition of claim 28,wherein said polymer is selected from the group consisting ofpoly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s,poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolicacid)s, polycaprolactone, polycarbonates, polyesteramides,polyanhydrides, poly(amino acids), polyorthoesters, polyacetyls,polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylenealkylate)s, copolymers of polyethylene glycol and polyorthoester,biodegradable polyurethanes, blends and copolymers thereof.
 32. Thecomposition of claim 28, wherein said bioactive agent is selected fromthe group consisting of proteins, nucleic acids, carbohydrates,peptides, LHRH agonists and synthetic analogs thereof, leuprolide,oxytocin, somatostatin and synthetic analogs thereof, small moleculepharmaceutical substances, immunogens, metabolic precursors capable ofpromoting growth and survival of cells and tissues, antineoplasticagents, hormones, antihistamines, cardiovascular agents, anti-ulceragents, bronchodilators, vasodilators, central nervous system agents andnarcotic antagonists.
 33. The composition of claim 28, wherein saidorganic ion is selected from the group consisting of pamoate,trifluoromethyl-p-toluate, cholate, 2-naphthalene sulfonate,2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate,3-hydroxy-2-naphthoate, 2-naphthoate, and salicylsalicylate.
 34. Thecomposition of claim 28, wherein the stoichiometry of the bioactiveagent relative to the organic ion ranges from about 1.0 to 1.5.
 35. Thecomposition of claim 28, wherein the bioactive agent is selected fromthe group consisting of octreotide, octreotide acetate andpharmaceutical equivalents thereof and the organic ion is pamoate. 36.The composition of claim 28, wherein the organic ion interacts with thebioactive agent to form a charged or neutral complex.